I. Problem/Condition.

A sizeable number of hospitalized patients are on anti-rheumatic medications. Agents include non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunomodulators such as azathioprine, and biologic agents such as infliximab.

These agents are associated with a variety of adverse events that could either represent the reason for inpatient admission or something that a clinician should watch for. This article will review the diagnostic approach and management strategy for common side effects related to anti-rheumatic medications.

A. What is the differential diagnosis for this problem?

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B. Describe a diagnostic approach/method to the patient with this problem

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1. Historical information important in the diagnosis of this problem.

The approach to a patient with a potential adverse effect involves awareness of mechanism of action of these drugs and recognizing that the side effects can present as multi-system involvement. The anti-rheumatic drugs reviewed in this article are as follows: NSAIDs, cyclooxygenase 2 (COX-2) inhibitors, glucocorticoids, hydroxychloroquine, sulfasalazine, methotrexate (MTX), leflunomide, cyclosporine, cyclophosphamide, etanercept, infliximab, adalimumab and anakinra, abatacept, rituximab, tocilizumab (TCZ), and tofacitinib.

Historically, MTX is a disease-modifying anti-rheumatic drug that is commonly used in the majority of patients as a long-term treatment. Time until 50% of users discontinuing this medication was more than 96 months, as compared to 43 months of sulfasalazine and 33 months for D-penicillamine.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

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3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

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C. Criteria for Diagnosing Each Diagnosis in the Method Above.

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D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

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A. Management of adverse effects of rheumatologic drugs.

Management involves triaging of these complications and recognizing a life-threatening event.

Monitoring of adverse drug reactions is essential and discontinuation of the offending medication should reverse most untoward consequences over time. Management of adverse drug reactions is mostly symptomatic, including providing supportive care for the specific system involved.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

Hypersensitivity reactions

Any of the anti-rheumatic medications can cause an allergic reaction, when started initially. Hypersensitivity reactions can occur within 2 hours of infusion of intravenous drugs. Symptoms include hives, skin rash (morbilliform), urticaria, bronchospasm, abdominal pain, diarrhea and life-threatening reactions such as angioedema and anaphylactic shock.

These are type I hypersensitivity reactions and are mediated by immunoglobulin E (IgE) and immunoglobulin G4 (IgG4). Management includes antihistamines and steroids. In severe cases, epinephrine (1:1000 for subcutaneous injections or 1:10000 for intravenous forms) and intubation might be required.

Delayed infusion reactions may represent mild type III (immune-mediated complex) reactions and may resemble serum sickness in the timing of their onset. These reactions develop between 1-14 days after treatment, but typically occur after 5-7 days. They can be associated with skin rash, diffuse joint pain, myalgias, fatigue, or fever.

Local injection site reactions are common adverse reactions, affecting up to 70% of the population receiving injectable forms of anti-rheumatic medications.

Etanercept, the first biological agent with Food and Drug Administration (FDA) approved labelling for use in rheumatoid arthritis (RA), has shown efficacy and can be associated with injection-site reactions. Anakinra (interleukin-1-receptor antagonist) used in severe RA can present with injection-site reactions causing ecchymosis and inflammation of the site, lasting up to 14-28 days.

Saline dressings and rotating the injection sites are helpful and application of topical steroids can decrease the inflammation.

Infectious complications

Glucocorticoids are important anti-inflammatory drugs used in the treatment of RA and systemic lupus erythematosis (SLE), and are also used to manage systemic complications such as nephritis and vasculitis. The mechanism of action is via repression of gene transcription-encoding inflammatory markers, and the adverse effects are mostly because of either positively- or negatively-regulating gene expression and involve several organ systems.

Glucocorticoids can affect both innate and acquired immunity. They suppress the immune system by decreasing the ability of leukocytes to adhere to vascular endothelium and to exit from the circulation.

They also inhibit the transcription of inflammatory cytokine, such as interleukin-1 and tumor necrosis factor (TNF)-alpha. Phagocytes are critical components of innate immunity and steroids inhibit phagocytosis by downregulating antigen presentation and expression of Class II human leukocyte antigen (HLA) molecules.

Patients on prednisone doses as low as 10 mg for more than 6 months can suffer from immune suppression. These patients are susceptible to viral (herpes zoster), fungal and bacterial infections, and also new onset or reactivation of tuberculosis. Reactivation of Strongyloides stercolais can occur. Helminthic and protozoan infections are unusual except in areas of the world where they are endemic.

Pneumocystis jirovecii is an opportunistic infection which can be seen in not only long-term low dose corticosteroid use, but also in short-term high dose usage. Once a day Trimethoprim/sulfamethoxazole should be started in patients who are immunocompromised to prevent Pneumocystis infection, and in acute settings, intravenous pentamidine is used. Adjunctive corticosteroids are not recommended in patients without human immunodeficiency virus (HIV) infection.

Etanercept is a TNF-alpha blocker and can lead to serious infections, which may result in hospitalization and/or death. Higher incidence of infections and disseminated (rather than local) infections are usually seen in patients receiving concomitant immunosuppressive agents (e.g., MTX or corticosteroids).

Infliximab (chimeric) and adalimumab (recombinant) are monoclonal antibodies that bind to TNF-alpha and are used in moderate to severe RA and also in ankylosing spondylitis. They mostly share the side effect profile of etanercept when it comes to infections.

Management of these infectious complications is based on early diagnosis of the specific infection and initiating treatment with specific anti-viral, anti-fungal or anti-bacterials. Purified protein derivative (PPD) skin testing should be done prior to starting patients on biological agents.

When there is prolonged productive cough, hemoptysis, weight loss, and fevers with night sweats in a patient, patients should be put in respiratory isolation and sputum should be tested for acid fast bacilli and imaging of chest done to rule out tuberculosis.

Cardiovascular complications

Uncontrolled hypertension is seen with NSAIDs use, selective COX-2 inhibitors, and corticosteroids. Some patients on NSAIDs and high dose steroids can rarely present with hypertensive emergencies. COX-2 inhibitors have also been associated with deep vein thrombosis, arrhythmias (tachycardia and bradycardia), and congestive heart failure. Celecoxib is also known to precipitate acute myocardial infarction, weight gain and peripheral edema.

In addition to uncontrolled hypertension, cardiovascular effects of steroids include worsening of lipid profile (increase in low density lipoprotein and triglycerides), acceleration of atherosclerosis, ischemic heart disease and congestive heart failure. These effects are probably secondary to fluid and sodium retention. There is also high risk of stroke and "all cause" mortality associated with use of glucocorticoids.

Management includes monitoring of fasting lipid profiles, blood pressure, assessing coronary artery disease based on symptoms, either through stress testing or angiography, and starting on statins, antihypertensives and antiplatelets depending on the need.

Pulmonary complications

Pulmonary complications such as bronchospasm and acute exacerbation of reactive airway disease are seen more commonly with aspirin use as compared to other NSAIDs. Patients can also present with a syndrome of fever, cough, dyspnea, infiltrates on chest x-ray, and peripheral eosinophilia. Management of these patients consists of starting low dose glucocorticoids and discontinuation of NSAIDs.

MTX-induced lung toxicity can have both acute and chronic presentations and is a serious and unpredictable event. Diagnosis is done by clinical history and radiographic findings, but the bronchoalveolar lavage plays an important role both in excluding infectious agents and in providing information for understanding the pathogenesis of lung injury.

The spectrum of pulmonary complications ranges from hypersensitivity pneumonitis (HSP), non-HSP pneumonitis, and P. jirovecii infection to bronchitis. Risk factors include patients with pre-existing lung disease represented by diffuse interstitial changes on chest X-ray, mild bronchial asthma or by pulmonary silicosis. Early diagnosis of MTX-induced lung injury is necessary as it is potentially reversible.

Leflunomide is a newer disease-modifying antirheumatic drug (DMARD) that reduces pyrimidine synthesis, thus decreasing rheumatoid inflammation. Leflunomide appears to be as effective as MTX, but can cause pulmonary artery hypertension (PAH). Management of PAH depends on the severity and is highly sub-specialised and warrants consulting a pulmonologist.

Hematologic complications

Although antiplatelet effects of NSAIDs, especially aspirin, is indicated in coronary artery disease, aspirin should be avoided in patients with thrombocytopenia, uremia and von Willebrand disease. NSAIDs decrease thromboxane A2 causing a decrease in platelet aggregation.

Other hematological effects of NSAIDs include neutropenia and interaction with warfarin, accentuating its effects and increasing international normalized ratio (INR). MTX, etanercept and other biological agents can cause severe pancytopenia secondary to bone marrow suppression. Leflunomide does not necessitate monitoring for bone marrow toxicity. Hydroxychloroquine, an antimalarial drug that is used in RA and SLE, can also cause pancytopenia and hemolysis in glucose-6-phosphatase deficiency (G6PD) patients and should be avoided in such patients.

Close monitoring of blood counts and decreasing the medication doses is helpful in preventing pancytopenia.

Immunological complications

Rarely, some patients on infliximab and adalimumab rarely develop antinuclear antibodies, antibodies to double-stranded deoxyribonucleic acid (DNA), and anti-infliximab antibodies, causing lupus-like disease. Henoch-Schonlein purpura is a small-vessel vasculitis and is seen with infliximab and with etanercept therapy and not with adalimumab. Discontinuation of these anti-rheumatic drugs can reverse the lupus-like manifestations but might take up to one year.

Celecoxib and other selective COX-2 inhibitors should be considered for patients who are candidates for NSAID therapy but at risk for GI bleeding. Even though they offer a superior safety profile as compared to more traditional NSAIDs, there is still a risk of GI bleeding - both upper and lower. Celecoxib occasionally increases liver enzymes and can rarely cause esophageal perforation and fulminant hepatic failure.

GI effects of steroids include dyspepsia, hepatic steatosis, peptic ulcer disease and increased risk of GI bleeding. The risk of GI bleeding increases 4-fold with concomitant use of NSAIDs.

GI complications caused by MTX include stomatitis, mouth ulcerations, liver toxicity - causing elevation of aminotransferases, autoimmune hepatitis, portal fibrosis, and cirrhosis. Long duration of therapy, alcohol intake, diabetes mellitus, obesity, and prior history of hepatitis B or C and age (greater than 60 years) have been found to be risk factors for the development of hepatic disease. Infliximab and adalimumab show increases in alanine transaminase especially when there is concomitant use with MTX.

GI side effects of hydroxychloroquine include nausea, vomiting, diarrhea, increased liver enzymes, and hepatic failure in some isolated cases.

Management of patients with GI bleeding includes hemodynamic stability, proton pump inhibitors and blood transfusion if necessary. Liver functions tests need to be monitored and if there is a suspicion of fulminant hepatic failure, assessment of the patient for liver transplantation should be initiated.

Neuropsychiatric complications

Central nervous system (CNS) effects of steroids include memory loss in geriatric patients. Psychosis can occur in some patients and is shown to be worse in patients with hypoalbuminemia. It can persist even after discontinuation of the steroid and responds well to antipsychotic medications. It is important to differentiate neuropsychiatric manifestations of SLE from steroid-induced psychosis.

In patients with SLE who are treated with ibuprofen and other NSAIDs of the phenylpropionic acid class who are presenting with altered mental status, aseptic meningitis should be considered.

CNS side effects of hydroxychloroquine include vertigo, headaches, ataxia, and neuromyopathy causing weakness and atrophy of proximal muscle groups. Etanercept is known to exacerbate some demyelinating diseases like optic neuritis, Guillain-Barre syndrome, transverse myelitis, and multiple sclerosis and causes either new onset or exacerbation of seizures.

Progressive multifocal leukoencephalopathy (PML) is a subacute central nervous system infection, caused by reactivation of John Cunningham virus. It is a rare, but devastating complication that can occur with the use of MTX, infliximab, rituximab, and leflunomide. Patients with lupus are at a higher risk for PML compared to patients with RA.

When admitting these patients, they should be under seizure precautions.

Severe hypokalemia, metabolic alkalosis and sometimes sudden death can be seen in cases of pulse steroid therapy where there is rapid infusion of high doses of steroids. Stopping the medication will usually revert the kidney function back to baseline, unless in severe cases where hemodialysis may be indicated.

Cutaneous complications

Skin effects of NSAIDs and hydroxychloroquine include less severe reactions such as urticaria, pseudoporphyria, and morbilliform rash, to life-threatening Steven-Johnson syndrome and toxic epidermal necrolysis. Also hydroxychloroquine typically is known to cause hyper pigmentation.

Stevens-Johnson syndrome is a medical emergency requiring inpatient treatment and is manifested by painful, erythematous or purplish rash on the skin and mucosal membranes, which can later slough off.

MTX-induced cutaneous manifestations, in acute settings, usually precede bone marrow suppression and are of two types: type I has painful ulcerations and necrosis of psoriatic lesions, seen in patients on higher doses of MTX. Type II is seen in patients on lower doses of the medication and in those having pre-existing skin conditions like stasis dermatitis. It takes longer to heal and the lesions are usually reversible after stopping the medication.

Endocrine complications

Glucocorticoids are known to cause chronic adrenal insufficiency (prednisone for at least a few weeks), obesity with cushingoid features (distribution of body fat with truncal obesity, buffalo hump and moon face), glucose intolerance, and worsening of diabetes mellitus in chronic settings. Monitoring of hemoglobin A1C (HgA1C) and fingersticks and managing with insulin therapy may be necessary.

Patients on chronic glucocorticoid therapy can sometimes present acutely with adrenal crisis manifested by hypotension, nausea and vomiting, hyponatremia, and hyperkalemia, and need hospitalisation. Therapy with intravenous fluids and dexamethasone should be initiated immediately if there is a suspicion of acute adrenal insufficiency without waiting for the laboratory results of serum cortisol or ACTH stimulation tests.

Risk of malignancy

Non-selective NSAIDs have been described in relation to increased risk of malignancies such as renal, colorectal, prostate, and breast cancers. Rarely, anakinra is associated with an increased risk of lymphoma in patients with RA. Black box warning for azathioprine and etanercept, adalimumab, and also other immunosuppressive agents shows development of lymphoma, hepatosplenic T-cell lymphoma and other malignancies, especially of the skin.

Musculoskeletal complications

Myopathy is seen in chronic steroid use and involves proximal muscles. This proximal muscle weakness should be differentiated from symptoms of dermatomyositis and polymyositis. Glucocorticoids reduce bone formation and increase bone resorption causing osteoporosis and increasing the risk of fractures. Vertebral fractures typically occur early on after exposure to glucocorticoids.

Replacing calcium, vitamin D, and starting patients on bisphosphonates is the treatment regimen for osteoporosis.

Other complications

Ophthalmological effects of steroids include cataract formation, precipitation of glaucoma and rarely, central serous chorioretinopathy, where there is fluid accumulation between the retina and the choroid. Hydroxychloroquine is known to cause ocular side effects including abnormal color vision, blurred vision and photophobia, optic disc pallor, and retinopathy, warranting yearly screening.

NSAID poisoning can be seen in either accidental or intentional overdose and is fairly uncommon. It is important to rule out other common ingredients like acetaminophen and salicylates when taking a history.

Acute mental status changes can be seen in severe poisoning. Severe anion-gap metabolic acidosis presenting with cardiac arrhythmias and electrolyte imbalances seen in NSAID poisoning, is due to tissue hypoxia causing high lactate levels and also due to weakly acidic NSAID metabolites.

Acute kidney disease could be secondary to severe papillary necrosis. Management includes stabilizing the patient with advanced cardiac life support (ACLS) protocol and then GI decontamination with charcoal based on the time of ingestion. After that management includes supportive care with fluid resuscitation, correction of acidosis and electrolyte imbalances and in rare instances hemodialysis. There is no specific antidote for NSAID poisoning.

Other medications used in rheumatology

Sulfasalazine contains active metabolite sulfapyridine which acts as a DMARD in patients with RA, and the side effects can be differentiated into idiosyncratic reactions - where the drug should be stopped and probably not used again, and dose-related side effects in which dose reduction can help resolve the problems.

Azathioprine antagonizes purine metabolism, interferes with cellular metabolism and mitosis and crosses the placenta. Side effects include fever, rash, bone marrow suppression causing pancytopenia, diarrhea and as it suppresses immunity it can cause multiple infections.

Hepatotoxicity is manifested by increasing transaminases and bilirubin and sinusoidal occlusive disease. Sweet’s syndrome (acute febrile illness with neutrophilic dermatosis) is an uncommon side effect of azathioprine.

Cyclosporine is used in RA and lupus nephritis, and acts by inhibiting the production and release of interleukin (IL) II and inhibits the IL II mediated activation of resting T-lymphocytes. Significant adverse effects include hypertension, peripheral edema and worsening of kidney function.

Renal biopsy might be indicated to differentiate between lupus nephritis and cyclosporine induced nephropathy in patients who are already on treatment for lupus nephritis. GI side effects include nausea, vomiting, GI bleeding (most common is upper) and pancreatitis.

Patients on cyclosporine are susceptible to multiple infections ranging from simple upper respiratory tract infections to pneumonias, renal abscess and sepsis syndrome. It can also worsen hypertension. If patients are on other concomitant immunosuppressive agents, the risk of skin cancer is increased.

Tacrolimus binds to an intracellular protein FK binding protein 12 (FKBP-12) thus inhibiting T-lymphocyte activation. Significant side effects include susceptibility to infections secondary to immunosuppressive action. GI effects include nausea, vomiting, diarrhea and ascites. It can worsen hypertension, peripheral edema and also can cause new-onset diabetes mellitus, which is more common in post-transplant patients rather than in patients with rheumatological diseases.

Hematological effects include pancytopenia and rarely, coagulation disorders and disseminated intravascular coagulation. Neuromuscular side effects include tremors, paresthesias, myoclonus, and rarely myasthenia gravis. Hypersensitivity reactions including anaphylaxis and shock have been reported.

Cyclophosphamide is an alkylating agent that suppresses cell division and DNA synthesis and is sometimes used unlabelled in severe RA, lupus nephritis and Wagener's granulomatosis. Significant side effects include sterility by interfering with oogenesis and spermatogenesis, pancytopenia, increased susceptibility to infections, and severe alopecia.

RA and SLE are diseases affecting commonly women of childbearing age and the usage of anti-rheumatic drugs in pregnancy and lactation should be considered on an individual basis. Hydroxychloroquine, sulfasalazine, NSAIDs, and aspirin are considered safe in pregnancy. Varying rates of preterm births, spontaneous abortions, and congenital defects are seen with various anti-rheumatic drugs, and their use is recommended only after consultation with a rheumatologist and obstetrician.

Disease-modifying anti-rheumatic nanomedicines (DMARNs) are a novice concept in treating RA. As they are both biocompatible and biodegradable and target inflamed joints selectively, they minimize the doses of drugs and prevent collateral damage to healthy tissues. Clinical trials are yet to begin however, and adverse reactions to these drug-loaded nanocarriers are unknown.

In conclusion, it is important to realize that anti-rheumatic medications are associated with a wide range of side effects. Early recognition and management are crucial for an optimum outcome. Consultation with a rheumatologist (and other sub-specialists) is sometimes warranted when patients do not respond to first line management of complications.